This proposal will study mechanisms responsible for the development of post radiation pulmonary fibrosis (PRPF). PRPF shares many common features with idiopathic pulmonary fibrosis, which has received extensive attention from investigators in pulmonary physiology and medicine. We will use this research, in addition to studies in radiobiology, as a basis for our study of pathways leading to PRPF. We hypothesize that changes in vascular permeability in the rat lung during the first month after radiation exposure are directly related to the development of fibrosis 6 to 12 months later. Changes in vasculr permeability may act as a cause of PRPF, due to leakage of material from the vasculature into the interstitium, or as an early measure of more general lung injury. We will test these hypotheses with six drugs to block different pathways to increased vascular permeability, and then monitoring subsequent development of PRPF. We have developed a unique, sensitive, and quantitative dual isotope technique to measure the lung vascular permeability surface area product (PS) to albumin. We have shown that lung PS increases immediately after whole thorax radiation, returns to normal, and then increases again approximately 20 days later. We will examine the effectiveness of six pharmacological agents in suppressing early changes in PS, and late changes in breathing rate in whole thorax irradiated rats and blood flow in hemithorax irradiated rats. The development of PRPF will be verified with histology. Each drug has been selected because of its ability to block a different step in the hypothesized pathway to increased vascular permeability and subsequent pulmonary fibrosis. We hypothesized that the early effects of these agents will define the importance of the corresponding blocked pathway and will predict the efficacy of the drug in reducing or preventing PRPF. We will then extend this approach by combining the most effective drugs to block the underlying process at several points. This should interrupt the cycle of cell activation and tissue injury that probably leads to end stage PRPF. Finally, the successful combination treatments will be modified and evaluated with multifraction radiotherapy to determine whether the sequence of events leading to fibrosis is different when lung injury occurs over an extended period of time. Post radiation pulmonary fibrosis is a serious complication in approximately 10% of patients with breast cancer or lung cancer who receive radiotherapy. These studies will aid our understanding of the development of radiation injury in the lung and should provide clinically relevant information on prevention of fibrosis.